Interleukin-2 (IL-2) is a potent stimulator of natural killer (NK) and T-cell proliferation and function (Morgan et al. (1976) Science 193:1007-1011). This naturally occurring lymphokine has been shown to have anti-tumor activity against a variety of malignancies either alone or when combined with lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) (see, for example, Rosenberg et al., N. Engl. J. Med. (1987) 316:889-897; Rosenberg, Ann. Surg. (1988) 208:121-135; Topalian et al., J. Clin. Oncol. (1988) 6:839-853; Rosenberg et al., N. Engl. J. Med. (1988) 319:1676-1680; and Weber et al., J. Clin. Oncol. (1992) 10:33-40). The anti-tumor activity of IL-2 has best been described in patients with metastatic melanoma and renal cell carcinoma using Proleukin®, a commercially available IL-2 formulation from Chiron Corporation, Emeryville, Calif. Other diseases, including lymphoma, also appear to respond to treatment with IL-2 (Gisselbrecht et al., Blood (1994) 83:2020-2022). However, high doses of IL-2 used to achieve positive therapeutic results with respect to tumor growth frequently cause severe side effects, including fever and chills, hypotension and capillary leak (vascular leak syndrome or VLS), and neurological changes (see, for example, Duggan et al., J. Immunotherapy (1992) 12:115-122; Gisselbrecht et al., Blood (1994) 83:2081-2085; and Sznol and Parkinson, Blood (1994) 83:2020-2022).
Metastatic renal cell carcinoma (RCC) is generally resistant to chemotherapy, either with single agents or with multiple agents in combination. Greater success has been seen with immunotherapy, particularly with the use of IL-2. Therapy with high dose intravenous IL-2 has resulted in objective tumor responses in approximately 15% of patients, some with long durability. However, the administration of high dose IL-2 is associated with capillary leak syndrome, which results in hypotension and reduced organ perfusion, which can be severe and sometimes fatal. These toxicities have generally restricted the use of IL-2 to a highly selected group of patients administered by physicians with significant experience in its administration. The use of lower-dose and subcutaneously administered regimens of IL-2 alone or in combination with other biologic agents, such as interferon-α, has been explored in an effort to develop a more broadly applicable therapy for this disease (see, for example, Nieken et al., Cancer Biother. Radiopharm. (1996) 11:289-295; Sleijfer et al., J. Clin. Oncol. (1992) 10:1119-1123; Lessoni et al., Anticancer Res. (2002) 22:1061-1-1064; Tourani et al., J. Clin. Oncol. (1998) 16:2505; and Schiller et al. Cancer Res. (1993) 53:1286-1292).
There remains a need for an improved therapy for treating patients having renal cell carcinoma that would reduce toxicity and improve therapeutic efficacy.